The onset mechanisms for inherited salt-losing tubulopathies

• Project/Area Number: 15K09691
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kobe University
• Principal Investigator: Nozu Kandai 神戸大学, 医学研究科, 准教授 (70362796)
• Co-Investigator(Kenkyū-buntansha): 飯島 一誠 神戸大学, 医学研究科, 教授 (00240854) ; 庄野 朱美 関西医科大学, 医学部, 研究員 (10535066)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 塩類喪失性尿細管機能異常症 / バーター症候群 / ギッテルマン症候群 / 遺伝性尿細管機能異常症 / 次世代シークエンサー / Copy number variation / 遺伝性低マグネシウム血症 / 遺伝性塩類喪失性尿細管機能異常症 / ターゲットシークエンス / 遺伝性高カルシウム尿性低カルシウム血症 / 遺伝性クロル下痢症 / 嚢胞性線維症

Outline of Final Research Achievements

We established a comprehensive diagnostic system for inherited salt-losing tubulopathies by targeted sequencing. As a result, we have performed genetic diagnosis of approximately 150 cases in three years, and now we have received analysis requests of 5-10 samples monthly. As a result, 1. Established the methodologies for Identification of deep intronic mutations in Gitelman syndrome, and for pathogenicity search of intra-intron mutations, 2. Established the novel methodology for detecting Copy Number Variation and identified HNF1B deletion which was causative variant for pseudo-Bartter syndrome. 3. We clarified the mechanism of the development of pseudo - Barter syndrome in hereditary hypercalcemic hypocalcemia.

Research Products

• [Int'l Joint Research] University of Southampton(United Kingdom)
• [Journal Article] Functional splicing analysis in an infantile case of atypical hemolytic uremic syndrome caused by digenic mutations in C3 and MCP genes (2018)
  • Author(s): Yamamura Tomohiko、Nozu Kandai、Ueda Hiroaki、Fujimaru Rika、Hisatomi Ryutaro、Yoshida Yoko、Kato Hideki、Nangaku Masaomi、Miyata Toshiyuki、Sawai Toshihiro、Minamikawa Shogo、Kaito Hiroshi、Matsuo Masafumi、Iijima Kazumoto
  • Journal Title: Journal of Human Genetics Volume: Epub ahead of print Issue: 6 Pages: 755-759
  • DOI: 10.1038/s10038-018-0436-9
  • Peer Reviewed
• [Journal Article] Development of ultra-deep targeted RNA sequencing for analyzing X-chromosome inactivation in female Dent disease (2018)
  • Author(s): Minamikawa S, Nozu K, Nozu Y, Yamamura T, Taniguchi-Ikeda M, Nakanishi K, Fujimura J, Horinouchi T, Shima Y, Nakanishi K, Hattori M, Kanda K, Tanaka R, Morisada N, Nagano C, Sakakibara N, Nagase H, Morioka I, Kaito H, Iijima K.
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 5 Pages: 589-595
  • DOI: 10.1038/s10038-018-0415-1
  • Peer Reviewed
• [Journal Article] Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases (2018)
  • Author(s): Nagano C, Nozu K, Morisada N, Yazawa M, Ichikawa D, Numasawa K, Kourakata H, Matsumura C, Tazoe S, Tanaka R, Yamamura T, Minamikawa S, Horinouchi T, Nakanishi K, Fujimura J, Sakakibara N, Nozu Y, Ye MJ, Kaito H, Iijima K
  • Journal Title: Clinical and Experimental Nephrology Volume: 印刷中 Issue: 4 Pages: 881-888
  • DOI: 10.1007/s10157-018-1534-x
  • NAID: 120006624236
  • Peer Reviewed
• [Journal Article] An in vitro splicing assay reveals the pathogenicity of a novel intronic variant in ATP6V0A4 for autosomal recessive distal renal tubular acidosis (2017)
  • Author(s): Yamamura Tomohiko、Nozu Kandai、Miyoshi Yuya、Nakanishi Keita、Fujimura Junya、Horinouchi Tomoko、Minamikawa Shogo、Mori Nobuo、Fujimaru Rika、Nakanishi Koichi、Ninchoji Takeshi、Kaito Hiroshi、Mariko Taniguchi-Ikeda、Morioka Ichiro、Matsuo Masafumi、Iijima Kazumoto
  • Journal Title: BMC Nephrology Volume: 18 Issue: 1 Pages: 353-353
  • DOI: 10.1186/s12882-017-0774-4
  • NAID: 120006377621
  • Peer Reviewed
• [Journal Article] Detection of a Splice Site Variant in a Patient with Glomerulopathy and Fibronectin Deposits (2017)
  • Author(s): Tsuji Yurika、Nozu Kandai、Sofue Tadashi、Hara Shigeo、Nakanishi Keita、Yamamura Tomohiko、Minamikawa Shogo、Nozu Yoshimi、Kaito Hiroshi、Fujimura Junya、Horinouchi Tomoko、Morisada Naoya、Morioka Ichiro、Taniguchi-Ikeda Mariko、Matsuo Masafumi、Iijima Kazumoto
  • Journal Title: Nephron Volume: 138 Issue: 2 Pages: 166-171
  • DOI: 10.1159/000484209
  • NAID: 120006867371
  • Peer Reviewed
• [Journal Article] A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome (2017)
  • Author(s): Nakanishi Keita、Nozu Kandai、Hiramoto Ryugo、Minamikawa Shogo、Yamamura Tomohiko、Fujimura Junya、Horinouchi Tomoko、Ninchoji Takeshi、Kaito Hiroshi、Morisada Naoya、Ishimori Shingo、Nakanishi Koichi、Morioka Ichiro、Awano Hiroyuki、Matsuo Masafumi、Iijima Kazumoto
  • Journal Title: European Journal of Medical Genetics Volume: 60 Issue: 12 Pages: 631-634
  • DOI: 10.1016/j.ejmg.2017.08.001
  • Peer Reviewed
• [Journal Article] Diagnostic strategy for inherited hypomagnesemia. (2017)
  • Author(s): Horinouchi T, Nozu K, Kamiyoshi N, Kamei K, Togawa H, Shima Y, Urahama Y, Yamamura T, Minamikawa S, Nakanishi K, Fujimura J, Morioka I, Ninchoji T, Kaito H, Nakanishi K, Iijima K.
  • Journal Title: Clin Exp Nephrol. Volume: 印刷中 Issue: 6 Pages: 1003-1010
  • DOI: 10.1007/s10157-017-1396-7
  • Peer Reviewed
• [Journal Article] Cryptic exon activation in SLC12A3 in Gitelman syndrome. (2017)
  • Author(s): Nozu K, Nozu Y, Nakanishi K, Konomoto T, Horinouchi T, Shono A, Morisada N, Minamikawa S, Yamamura T, Fujimura J, Nakanishi K, Ninchoji T, Kaito H, Morioka I, Taniguchi-Ikeda M, Vorechovsky I, Iijima K
  • Journal Title: J Hum Genet. Volume: 62 Issue: 2 Pages: 335-337
  • DOI: 10.1038/jhg.2016.129
  • NAID: 40021065185
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Acute kidney injury in type 3 Bartter syndrome: Angiotensin-converting enzyme inhibitors as a cause. (2016)
  • Author(s): Nagao R, Suzuki S, Kawashima H, Nozu K, Iijima K
  • Journal Title: Pediatr Int Volume: 58 Issue: 12 Pages: 1373-1374
  • DOI: 10.1111/ped.13100
  • Peer Reviewed
• [Journal Article] 腎・泌尿器 Gitelman症候群 (2016)
  • Author(s): 野津寛大
  • Journal Title: 小児科診療 Volume: 79 Pages: 300-300
• [Journal Article] 腎・泌尿器 Bartter症候群 (2016)
  • Author(s): 野津寛大
  • Journal Title: 小児科診療 Volume: 79 Pages: 294-294
• [Journal Article] Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics (2016)
  • Author(s): Matsunoshita N, Nozu K, Shono A, Nozu Y, Fu XJ, Morisada N, Kamiyoshi N, Ohtsubo H, Ninchoji T, Minamikawa S, Yamamura T, Nakanishi K, Yoshikawa N, Shima Y, Kaito H, Iijima K
  • Journal Title: Genetics in Medicine Volume: 18 Issue: 2 Pages: 180-188
  • DOI: 10.1038/gim.2015.56
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathogenesis of hypokalemia in autosomal dominant hypocalcemia type 1. (2016)
  • Author(s): Kamiyoshi N, Nozu K, Urahama Y, Matsunoshita N, Yamamura T, Minamikawa S, Ninchoji T, Morisada N, Nakanishi K, Kaito H, Iijima K.
  • Journal Title: Clin Exp Nephrol. Volume: 20 Issue: 2 Pages: 253-257
  • DOI: 10.1007/s10157-015-1160-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bartter症候群、Gitelman症候群 (2015)
  • Author(s): 松野下夏樹 野津寛大 飯島一誠
  • Journal Title: 日本腎臓学会誌 Volume: 57 Pages: 743-750
  • Peer Reviewed
• [Journal Article] Bartter症候群・Gitelman症候群:遺伝性塩類喪失性尿細管機能異常症 (2015)
  • Author(s): 野津寛大
  • Journal Title: 内科 Volume: ６ Pages: 1039-1039
• [Presentation] 尿細管機能異常と電解質 (2017)
  • Author(s): 野津寛大
  • Organizer: 第7回東北小児内分泌講演会
  • Invited
• [Presentation] 遺伝性腎疾患の研究から学んだ大切なこと－研究の楽しさと臨床へのフィードバック－ (2017)
  • Author(s): 野津寛大
  • Organizer: 第120回日本小児科学会学術集会
  • Invited
• [Presentation] ネフローゼ症候群と遺伝子-どこまで分かっているか、どのような場合遺伝子診断が必要か (2016)
  • Author(s): 野津寛大
  • Organizer: 第52回日本小児腎臓病学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2016-07-07
  • Invited
• [Presentation] 特発性ネフローゼ症候群の成因と治療 (2016)
  • Author(s): 野津寛大
  • Organizer: 第52回日本小児腎臓病学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2016-07-07
  • Invited
• [Presentation] 男女共同参画「genderと腎-遺伝性腎疾患」 (2016)
  • Author(s): 野津寛大、飯島一誠
  • Organizer: 第60回日本腎臓学会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-18
  • Invited
• [Presentation] Gene targeting therapy for Alport syndrome (2016)
  • Author(s): Kandai Nozu
  • Organizer: 2016 Pediatric Academic Societies Meeting
  • Place of Presentation: Baltimore
  • Year and Date: 2016-05-02
  • Int'l Joint Research / Invited
• [Book] 12.Bartter症候群、Gitelman症候群 (2015)
  • Author(s): 野津寛大
  • Total Pages: 629
  • Publisher: 医学書院